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Biomedical subjects

R H Belmaker

Publications and source records attributed to R H Belmaker.

At least 55 records · Page 3Linked to original sources
PubMed2002

3'(2')-phosphoadenosine 5'-phosphate phosphatase is reduced in postmortem frontal cortex of bipolar patients.

OBJECTIVE: 3'(2')-Phosphoadenosine 5'-phosphate (PAP) phosphatase is a novel lithium (Li) inhibitable enzyme. Thus the enzyme seemed an important candidate for studies of the molecular etiology of bipolar disorder. METHODS: RT-PCR, Western-blot analysis and Pi liberation were used to measure PAP phosphatase mRNA levels, protein levels and enzyme activity (respectively) in postmortem frontal cortex specimens of bipolar patients versus normal subjects. RESULTS: The PAP phosphatase protein levels were 24% significantly lower in bipolar patients than in normal subjects. PAP phosphatase mRNA levels and enzymatic activity did not differ between normal controls and bipolar patients. CONCLUSIONS: Abnormality of PAP phosphatase in bipolar patients offers a new direction for study of bipolar disorder etiology.

Adult↗
PubMed2002

Epi-inositol regulates expression of the yeast INO1 gene encoding inositol-1-P synthase.

Myo-inositol exerts behavioral effects in animal models of psychiatric disorders and is effective in clinical trials in psychiatric patients. Interestingly, epi-inositol exerts behavioral effects similar to myo-inositol, even though epi-inositol is not a substrate for synthesis of phosphatidylinositol. We postulated that the behavioral effects of epi-inositol may be due to its effects on gene expression. Yeast INO1expression was measured in northern blots. INM1 was determined by beta-galactosidase activity in a strain containing the fusion gene INM1-lacZintegrated into the genome. Epi-inositol affects regulation of expression of the INO1 gene (encoding inositol-1-P synthase), even though it cannot support growth of an inositol auxotroph (suggesting that, as in mammalian cells, it is not incorporated into phosphatidylinositol). Like myo-inositol, although to a lesser extent, epi-inositol causes a significant reduction in INO1 expression, and reverses the lithium- or valproate-induced increase in INO1 expression. However, it does not affect regulation of INM1 (encoding inositol monophosphatase), the expression of which is up-regulated by myo-inositol. The observed regulatory effects of epi-inositol on expression of the most highly regulated gene in the inositol biosynthetic pathway may help to explain how this inositol isomer can exert behavioral effects without being incorporated into phosphatidylinositol.

Anticonvulsants↗
PubMed2002

Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder.

OBJECTIVE: Studies have reported that countries with high rates of fish oil consumption have low rates of depressive disorder. The authors studied a specific omega-3 fatty acid, the ethyl ester of eicosapentaenoic acid (E-EPA), as an adjunct to treatment for depressive episodes occurring in patients with recurrent unipolar depressive disorder who were receiving maintenance antidepressant therapy. METHOD: Twenty patients with a current diagnosis of major depressive disorder participated in a 4-week, parallel-group, double-blind addition of either placebo or E-EPA to ongoing antidepressant therapy. Seventeen of the patients were women, and three were men. RESULTS: Highly significant benefits of the addition of the omega-3 fatty acid compared with placebo were found by week 3 of treatment. CONCLUSIONS: It is not possible to distinguish whether E-EPA augments antidepressant action in the manner of lithium or has independent antidepressant properties of its own.

Adult↗
PubMed2002

Personality genetics, 2002.

The study of the genetics of personality looks for effects of genetic differences on psychological differences between people. The most replicated associations have been between the dopamine D4 receptor gene and "novelty seeking" and between the serotonin reuptake transporter gene and anxiety. But even these reports are controversial, and their effects are too small to add to existing scientific theories or allow for clinical use in psychological counseling. Simultaneously studying three polymorphisms suggests that gene-gene interactions are partly responsible for these difficulties. Recently a linkage of anxiety-related traits to chromosome 8p21-23 has been replicated, and we may be close to isolating relevant genes in the region. But uncertainty about psychological phenotypes remains, and it is not clear whether future breakthroughs will require studies of thousands of genes in very large samples, or revolutions in the current assumptions and methods of personality genetics.

Genetic Linkage↗
PubMed2001

Low GSK-3 activity in frontal cortex of schizophrenic patients.

Glycogen synthase kinase-3 (GSK-3) (EC 2.7.1.37) is a protein kinase highly abundant in brain and involved in signal transduction cascades of multiple cellular processes, particularly neurodevelopment. Two forms of the enzyme, GSK-3alpha and -3beta have been previously identified. We have previously reported reduced GSK-3beta protein levels in postmortem frontal cortex of schizophrenic patients. In an attempt to explore whether reduction of GSK-3beta levels is brain region specific we examined it in occipital cortex. In order to find out if the reduction in frontal cortex is reflected in altered activity we measured GSK-3 enzymatic activity in this brain region. Western-blot analysis of GSK-3beta was carried out in postmortem occipital cortex of 15 schizophrenic, 15 bipolar, and 15 unipolar patients, and 15 normal controls. GSK-3 activity was measured by quantitating the phosphorylation of the specific substrate phospho-CREB in the frontal cortex specimens. GSK-3beta levels in occipital cortex did not differ between the four diagnostic groups. GSK-3 activity in the frontal cortex of schizophrenic patients was 45% lower than that of normal controls (0.196+/-0.082 and 0.357+/-0.084 pmol/mg proteinxmin, respectively; Kruskal-Wallis analysis: chi-square=8.27, df=3, p=0.04). The other two diagnostic groups showed no difference from the control group. Our results are consistent with the notion that schizophrenia involves neurodevelopmental pathology.

Bipolar Disorder↗
PubMed2001

No evidence for linkage by transmission disequilibrium test analysis of microsatellite marker D22S278 and schizophrenia in a Palestinian Arab and in a German population.

Linkage for a schizophrenia susceptibility locus on chromosome region 22q12-q13 was initially suggested by independent studies from two groups and confirmed in a combined analysis of data for the microsatellite marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. In addition to these reports of linkage to schizophrenia on chromosome 22, bipolar disorder has also been linked to markers in this chromosomal region. We now report results from an analysis of 223 Palestinian Arab trios from three different centers in Israel and Palestine using the allele-wise extended transmission disequilibrium test for multiallelic markers. No evidence for linkage is observed in the entire group or in any of the three centers (entire group: chi-square = 5.59, P = 0.78, df = 9; Afula: chi-square = 6.51, P = 0.48, df = 7; Bethlehem: chi-square = 14.11, P = 0.12, df = 9; Beersheva: chi-square = 7.04, P = 0.32, df = 6). Additionally, we examined D22S278 in a group of 114 schizophrenic German triads and failed to observe evidence for linkage (chi-square = 8.13, P = 0.42, df = 8df).

Alleles↗
PubMed2001

A family-based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia.

The 5HT2C receptor has a high affinity for clozapine, a nontypical neuroleptic, and has therefore been postulated to play a role in mediating negative symptoms and neuroleptic response in schizophrenia. In the current study, the Cys23Ser 5HT2C serotonin receptor polymorphism was examined for linkage to schizophrenia by genotyping 207 nuclear families consisting of both parents and schizophrenic child and using the transmission disequilibrium test to examine possible preferential transmission of these alleles from 68 heterozygous mothers to their ill child. No evidence was obtained for preferential transmission of the Cys23Ser 5HT2C alleles in schizophrenia in either of the two main ethnic groups examined (German and Palestinian Arab) or in the combined cohort (TDT chi-square = 0.00, NS).

Adolescent↗
PubMed2001

The antidepressant activity of inositol in the forced swim test involves 5-HT(2) receptors.

The effect of inositol as an antidepressant was previously demonstrated in both animal models of depression-like behavior and in clinical trials. Unlike most antidepressant drugs, inositol does not have a clear target in the synapse and was not demonstrated to alter monoamine levels in the brain. The present study attempted to draw a psychopharmacological profile of inositol's behavioral effects by exploring the interactions between the drug and specific receptor agonists and antagonists in the forced swim test. Rats received inositol treatment (or control) in combination with the serotonergic metabolism inhibitor PCPA or with the noradrenergic neurotoxin DSP-4. Results indicated that PCPA but not DSP-4 abolished the ability of inositol to cause a reduction in immobility time in the forced swim test. In mice, the specific 5-HT(2A)/5-HT(2C) antagonist ritanserin, but not the 5-HT(1A)/5-HT(1B)/beta adrenergic antagonist pindolol, abolished inositol's effect in the forced swim test. The 5-HT(2A)/5-HT(2C) agonist DOI and the 5-HT(1A) agonist 8-OH-DPAT did not have any significant effects on inositol's activity. The present data indicates that the antidepressant effect of inositol may involve 5-HT(2) receptors. It is thus possible that the effects of reuptake antidepressant drugs and the effects of inositol may have a common final pathway.

Animals↗
PubMed2001

Effect of inositol on bulimia nervosa and binge eating.

OBJECTIVES: This study aimed to determine whether inositol has therapeutic value in patients with bulimia nervosa and binge eating. METHOD: A double-blind crossover trial using 18 g inositol versus placebo was performed in 12 patients for 6 weeks in each arm. RESULTS: Inositol was significantly better than placebo on the Global Clinical Impression, the Visual Analogue Scale, and the Eating Disorders Inventory. DISCUSSION: Inositol is as therapeutic in patients with bulimia nervosa and binge eating as it is in patients with depression and panic and obsessive-compulsive disorders. This increases its parallelism with serotonin selective reuptake inhibitors.

Adult↗
PubMed2001

The effects of inositol treatment in animal models of psychiatric disorders.

Clinical trials indicate that inositol may be effective in the treatment of patients with depression, panic disorder and obsessive compulsive disorder (OCD), but not in the treatment of patients with schizophrenia, Alzheimer's disease, ADHD or autism. This spectrum of clinical action parallels that of serotonin selective reuptake inhibitors (SSRIs), but inositol is a precursor in the phosphatidylinositol cycle, a second messenger system distal to the receptor for 5HT-2. To study its mechanism of therapeutic action there is a need to test inositol's activity in animal models of psychopathology. In rats, chronic inositol was demonstrated to increase activity levels, reduce immobility time in the forced swim test and in the reserpine-induced hypoactivity models of depression, and reduce anxiety-like behaviors in the elevated plus-maze. The reduction in anxiety-like behaviors appears to be related to baseline levels of activity. Inositol treatment was not observed to have any effect on amphetamine-induced hyperactivity, apomorphine-induced stereotypy, or on the performance of memory tasks by monkeys. Clinical controlled trials of inositol in patients with depression, panic disorder, and OCD were small, and positive psychoactive effects in animals clearly strengthen the case for further clinical trials and potential for general therapeutic use in humans.

Affect↗
PubMed2001

The mechanism of lithium action: state of the art, ten years later.

Lithium is an effective drug for both treatment and prophylaxis of bipolar disorder. However, the mechanism of lithium action is still unknown. The inositol depletion hypothesis is supported by biochemical and behavioral data in rats, but primate inositol levels are higher than in rodents and may obviate the effects of depletion. Inhibition of 5HT autoreceptors by lithium is supported by biochemical and behavioral data in rats but would seem more related to lithium's antidepressant than to its antimanic or prophylactic effects. Lithium induces increases in levels of the anti-apoptotic factor Bcl-2. This effect could be most relevant for treatment of neurodegenerative disorders. Lithium inhibits glycogen synthase kinase-3, which is involved in a wide range of signal transduction pathways. However, this lithium effect occurs at high concentrations and may be more relevant for its toxic effect. Lithium in low concentrations induces accumulation of PAP, which affects several cellular processes including RNA processing. However, PAP phosphatase is present more in peripheral tissues than in brain. This lithium effect could explain some of its peripheral side effects. Chronic lithium administration upregulates glutamate reuptake and thus decreases glutamate availability in synapse. Glutamate is an excitatory neurotransmitter and its reduction could exert an antimanic effect. Biochemical and clinical experiments are necessary to determine the key mechanism of lithium efficacy in treatment and prophylaxis of affective disorders.

5'-Nucleotidase↗
PubMed2001

Transcranial magnetic stimulation in an amphetamine hyperactivity model of mania.

OBJECTIVES: Transcranial magnetic stimulation (TMS) of the brain has been reported to have therapeutic effects in mania, as well as depression. TMS has previously been reported to have effects similar to those of electroconvulsive shock in rat models of depression. METHODS: We, therefore, studied TMS in amphetamine-induced hyperactivity as a rat model of mania. RESULTS: While two and seven daily TMS sessions significantly reduced activity after amphetamine, twice-daily TMS for 7 days enhanced activity after amphetamine. CONCLUSIONS: The results suggest that TMS treatment to rats interacts with the effects of amphetamine; the specific effects may be dependent on the schedule of treatment.

Amphetamine↗
PubMed2001

Inositol treatment has no effect on the dexamethasone suppression test.

The dexamethasone suppression test (DST) is a widely studied state marker for endogenous depression. Several drugs cause false positives or negatives in this test. Since inositol is a new treatment for depression it is important to determine if it causes artifacts in the DST. Five patients with major depression diagnosed according to DSM-IV underwent a dexamethasone suppression test before and after one and two weeks of 12 grams daily inositol treatment. Three normal subjects underwent the same procedure before and after one week of inositol treatment. Four depressed patients and all three normal subjects demonstrated pretreatment dexamethasone suppression of plasma cortisol. One or two weeks of inositol treatment had no effect on post-dexamethasone cortisol plasma levels in patients or subjects. One depressed patient was a non-suppressor before treatment and continued to show elevated post dexamethasone cortisol levels after one week of inositol treatment. However, after two weeks on inositol, when substantial clinical improvement was noted, he converted to a normal DST. Chronic inositol treatment does not seem to induce false positive DST results.

Adult↗
PubMed2001

Inositol monophosphatase activity in brain and lymphocyte-derived cell lines of bipolar patients.

BACKGROUND: Inositol monophosphatase (IMPase) activity was reported to be low in lymphocyte-derived cell lines of bipolar patients. METHODS: IMPase activity was measured spectrophotometrically as inorganic phosphate liberated from inositol-1-phosphate. RESULTS: The previously reported reduction was replicated in a new, small group of bipolar patients. The reduction is not present in cell lines of unipolar or schizophrenic patients. IMPase activity in postmortem frontal and occipital cortical samples of unipolar, bipolar and schizophrenic patients was not different from controls. CONCLUSIONS: A reduction in lymphocyte-derived IMPase activity without a parallel reduction in cortical IMPase activity could be due to the fact that most leukocyte IMPase activity is the product of the IMPA-2 gene.

Adult↗
PubMed2001

Evidence for the effectiveness of olanzapine among patients nonresponsive and/or intolerant to risperidone.

BACKGROUND: This multicenter, open-label study evaluated the efficacy and safety of olanzapine in patients with schizophrenia who had been nonresponsive or intolerant to a course of risperidone (mean duration of risperidone treatment = 46.3 days). METHOD: A total of 34 patients with DSM-III-R and ICD-9 schizophrenia entered this trial. Twenty-five patients were nonresponsive to previous risperidone treatment, 6 patients were intolerant to the risperidone treatment, and 3 patients listed both reasons for discontinuation of risperidone. Patients were treated across a dose range of 5 to 25 mg/day of olanzapine. The primary efficacy variable was baseline to endpoint change in Positive and Negative Syndrome Scale (PANSS) score. Safety was assessed using the Clinical Global Impressions-Severity of Illness scale. RESULTS: Improvement from baseline PANSS score (mean +/- SD PANSS score = 119.4 +/- 26.9) was evident at the week-6 midpoint (-22.2 +/- 19.5) and at the week-14 endpoint (-28.7 +/- 22.3). On average, severity ratings were reduced from baseline by 25% after 14 weeks of olanzapine therapy. Twenty olanzapine-treated patients (58.8%) achieved the a priori-defined response criterion of > or = 20% reduction in PANSS total score. Among patients who met the response criterion, 50% (10/20) had done so by the fourth week. These clinical improvements occurred across a broad range of symptom domains and included reductions in PANSS positive, negative, general psychopathology, and mood subscores. No statistically significant differences were found on any efficacy measure at any visit between the patients who were nonresponsive to risperidone compared with those who were intolerant to risperidone. Olanzapine was well tolerated, with no subject discontinuing early owing to an intolerable adverse event that could be conclusively linked to olanzapine. CONCLUSION: The results of this open-label study suggest that olanzapine may be an effective alternative for schizophrenic patients who are nonresponsive and/or intolerant to risperidone treatment. Moreover, the results underscore the differential pharmacology that exists among the newer antipsychotic agents.

Adult↗
PubMed2001

[Animal models of psychiatric diseases: possibilities, limitations, examples and demonstration of use].

Animal models of psychopathology serve as a central tool for psychopharmacologists in their attempts to develop new, more efficient medications for psychiatric disorders, and in the efforts to explore the mechanisms of conventional and novel drugs. The development of efficient models for psychiatric diseases is complicated since the mechanisms of the disorders are not clear, major parts of the diagnosis depend on verbal communication with the patient and many of the symptoms are expressed mainly through the subjective experiences of the afflicted individual. Inspite of these difficulties, effective models were developed for most psychiatric diseases. The development of such models is based on their validation in three different dimensions: face validity--behavioral similarities between the model and the disorder; construct validity--similarities between the mechanisms related to the model and a mechanistic theory of the disease; predictive validity--that the model response to the conventional medications that are effective in the disease and will not respond to drugs that are not effective in the disease. The present paper presents three known models of depression; each induced in a different way and therefore represents a group of models: Reserpine-induced hypoactivity--represents the group of pharmacologically induced models. Forced swim test--represents the group of behaviorally induced models. Flinders Sensitive Line--represents the group of genetically induced models. The use of these models in an attempt to examine the range of action of a new potential antidepressant and its mechanisms of action is demonstrated with a recent set of experiments with inositol.

Animals↗